Academic Research Enhancement Award (R15) Action Mechanisms of Resveratrol in Somatic Longevity and Reproductive System PROJECT SUMMARY Resveratrol (RSV) has emerged as a highly effective, longevity-promoting small molecule. Although several studies have shown that RSV extends lifespan through Sirtuin (a family of NAD+-dependent deacetylases)-dependent pathways, there is still much controversy surrounding the underlying mechanisms of this lifespan extension effect. Using the nematode Caenorhabditis elegans (C. elegans), we found that RSV-mediated longevity largely depends on both SIR-2.1 (a Sirtuin/SIRT1 homolog) and MPK-1 (an ERK/MAPK homolog). Specifically, RSV partially extended lifespan in single mutant worms lacking either SIR-2.1(SIRT1) or MPK-1(ERK), compared to that of wild-type worms. However, RSV-mediated longevity was completely abolished in double mutant worms lacking both SIR-2.1(SIRT1) and MPK-1(ERK). In addition to somatic longevity, we found that RSV has both positive and negative effects on the reproductive system depending on the genetic context ? RSV promotes both reproductive longevity via SIR-2.1(SIRT1) and the formation of MPK-1(ERK)-associated germline tumors in a specific genetic mutant. In this proposal, we aim to investigate the molecular mechanism of how RSV cooperates with genetic regulators, including SIR-2.1(SIRT1) and MPK-1(ERK), to control somatic longevity and reproductive system (i.e., reproductive longevity and tumorigenesis). Importantly, SIR-2.1(SIRT1) and MPK-1(ERK) activate DAF- 16 (a family of the FOXO transcription factor) and SKN-1 (a family of the NRF2 transcription factor), respectively. Therefore, we will test the hypothesis that RSV controls somatic longevity (Aim 1) and the reproductive system (Aim 2) through both SIR-2.1(SIRT1)DAF16(FOXO) and MPK-1(ERK)SKN-1(NRF2) pathways. Overall, the proposed project will enrich the infrastructure for research and education as well as increase the participation of underrepresented groups, which fulfills the purpose of the NIH-AREA (R15) grant. In addition, our findings in a simple organism will provide new mechanistic insights into the controversial effects of RSV on longevity, but will also have important implications regarding RSV utilization to enhance the prognosis of aging-associated diseases in vertebrates, where such in vivo methods are not feasible or practical.